To clarify the manifestations of the genetic component of human diabetes, a prospective study of offspring of two diabetic parents and apparently unaffected monozygotic twins with a diabetic twin-mate will be continued and expanded. Emphasis will be placed upon the evolution, nature and progression of overt and occult diabetes in these subjects. Serum insulin, plasma glucagon and serum growth hormone responses and relationships will be quantified. Abnormalities in lipid metabolism will be defined and additional quantification of the nature of the hyperlipidemia in selected groups will be studied. Appropriate subgroups of diabetic proband parents or twins classified into young onset, old onset, juvenile onset type and maturity onset type will be made and intragroup comparisons performed. Mechanisms of insulin secretion in these groups will be pursued with studies involving administration of various hexoses other than glucose and evaluation of gastric ihibitory polypeptide. Muscle capillary basement membrane thickness evaluated by electron microscopy and hemoglobin A1c estimations will be performed, interrelated to each other and to the type of glucose tolerance, insulin response and glucagon response of specified subgroups and to appropriate normal controls. By these studies, the nature, magnitude and interrelationships of a number of phenotypes related to early diabetes will be made leading to a better understanding of the expressive mode of the genetic components and their interrelationships in the pathogenesis of human diabetes.